Project Summary Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that can cause severe lifelong impairment for affected individuals. An increase in the prevalence of ASD has been documented worldwide, which has major public health implications because of the substantial familial and societal resources required to provide long-term services to those who are affected. Much remains to be discovered about the causes of ASD, including risk and protective factors for its occurrence and presentation, as well as about phenotypic variations and co-occurring conditions, and how these interact, in persons affected by ASD. In response to growing public health concerns, the Children's Health Act of 2000 mandated CDC to establish ASD surveillance and research programs that address the magnitude, incidence, and causes of ASD and related developmental disabilities. The Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDREs) were established at six national sites (California, Colorado, Georgia, Maryland, North Carolina, and Pennsylvania) to fulfill this mandate and are currently carrying out the second phase of the Study to Explore Early Development (SEED), a population-based case-control study. The objectives of SEED are to examine ASD phenotypic variation, including clustering of core symptoms, cognitive status, and presence of co-morbidities; genetic variation and gene-environment interaction (GxE); and infection, immune function, autoimmunity, hormonal factors and maternal reproductive characteristics that may influence ASD occurrence or presentation. Data collection for SEED includes assessments of development through standardized instruments and pre- and perinatal health and environment via interviews, medical record review, self-administered questionnaires, and biologic samples. As of December 2015, SEED 1 & 2 had completed data collection on 4652 families - 1341 with ASD, 1722 with other developmental disorders, and 1589 general population controls. This proposal seeks to carry out SEED 3, enrolling 625 additional children in each study group. The combined greater sample size will enable well-powered assessment of SEED hypotheses, particularly for phenotypic subgroups and GxE interactions. Given the infrastructure in place at Colorado and the other CADDRE sites, and their extensive experience successfully implementing SEED 1 & 2, SEED 3 can be quickly implemented in Colorado and throughout the network, creating a combined SEED sample of clinical, risk factor, and biological specimens and data on over 6500 families. SEED will be the largest study of ASD of its kind, making significant contributions to our understanding of the complex autism phenotype and identifying potential risk and protective factors for ASD to inform future development of interventions and treatments.